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Inhalation solutions – which one are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulizers

      Abstract

      Therapy of chronic respiratory diseases often involves inhalation therapy with nebulizers. Patients often attempt to shorten the time consuming administration procedure by mixing drug solutions/suspensions for simultaneous inhalation. This article considers the issue of physico-chemical compatibility of admixtures of drug solutions/suspensions in nebulizers.
      A search of databases, prescribing information and primary literature was conducted to locate literature concerning the physico-chemical compatibility of inhalation solutions/suspensions. This was supplemented by telephone interviews.
      Admixtures of albuterol with ipratropium and/or cromolyn, of albuterol and budesonide, or tobramycin, or colistin are physico-chemically compatible. Physico-chemical compatibility has been demonstrated for admixtures of cromolyn with albuterol and/or ipratropium and for admixtures of cromolyn and budesonide. Admixtures of budesonide with ipratropium and/or fenoterol, and admixtures of budesonide and albuterol, or cromolyn are physico-chemically compatible. Both cromolyn and colistin are incompatible with benzalkonium chloride. Admixtures should be prepared from inhalation solutions/suspensions formulated without preservatives.
      Besides studies of the physico-chemical compatibility, the aerodynamic behaviour of physico-chemical mixtures needs to be studied before a final recommendation of simultaneous nebulization of compatible admixtures can be made.

      Keywords

      1. Introduction

      For patients suffering from chronic airways disease, e.g. cystic fibrosis (CF) or asthma, inhalation of aerosolized medications is the mainstay of therapy. Although inhalation therapy with hand-held inhalers is more common, nebulizers are also widely used. In nebulizers ultrasound or a jet stream of compressed air is used to convert the drug solution/suspension into an aerosol. Aerosolized droplets or particles should be 1 to 5 μm diameter in size. Larger particles will deposit in the upper airways; smaller particles may be exhaled [
      • Boe J.
      • Dennis J.H.
      • O'Driscoll B.R.
      • Bauer T.T.
      • Carone M.
      • Dautzenberg B.
      • et al.
      For the society task force on the use of nebulizers. European Respiratory Society guidelines on the use of nebulizers.
      ].
      Drug substances commonly used for inhalation therapy comprise albuterol, ipratropium, cromolyn, budesonide, tobramycin, colistin and the rhDNAse dornase alfa (Table 1). Inhalation therapy takes 10 to 15 min and afterwards the nebulizer must be cleaned, dried and reassembled. Inhalation of several nebulizable medications may take up to 45 min or longer. It is quite evident that patients need strict discipline to adhere to this time-consuming daily procedure. Mixing nebulizable medications for simultaneous inhalation is an obvious way to reduce the duration of nebulization and is a commonly used procedure. Interviews conducted at the CF centre of our university hospital identified 40 patients, who took more than one nebulizable medication daily. Eight of them routinely mixed nebulizable medications, which are known to be incompatible. Knowledge of the physico-chemical compatibility of admixtures of nebulization products is an important issue. This review aims to provide a literature overview and recommendations for mixing nebulizable medications.
      Table 1Overview of inhalation solutions/suspensions
      Drug substanceExamples for brandsPossibly relevant excipients
      AlbuterolSultanol Fertiginhalat® (unit dose) (Germany)No known relevant excipients
      Sultanol® (Germany)BAC
      Proventil® 0.5% (US)BAC
      IpratropiumAtrovent® LS (Germany)BAC, EDTA
      Atrovent® Inhalation solution (unit dose)No known relevant excipients
      CromolynIntal®No known relevant excipients
      BudesonidePulmicort®EDTA
      TobramycinTobi®No known relevant excipients
      Gernebcin® (Germany)Sodium disulfit
      Dornase alfaPulmozyme®No known relevant excipients
      ColistinCOLISTIN® zur Inhalation (Germany)No known relevant excipients
      Promixin® Powder (UK)No known relevant excipients
      OrciprenalineAlupent® Inhalation Solution (no longer available)Sodium disulfit , EDTA
      TerbutalineBricanyl® 1% Solution (Germany)Chlorbutanol, EDTA
      Ipratropium plusBerodual LS (Germany)BAC, EDTA
      FenoterolDuovent® (unit dose) (UK)No known relevant excipients
      AcetylcysteineFluimucil® (Germany)EDTA
      Mucomyst® (US)Not known
      AmbroxoleMucosolvan® Inhalation Solution 15 mg/2 mL (Germany)BAC
      BAC=benzalkonium chloride, EDTA=ethylenediaminetetraacetic acid.

      2. Material and methods

      In order to get information about the compatibility/stability of combinations of nebulizer solutions in inhalation therapy the pharmaceutical and medical literature databases “International Pharmaceutical Abstracts” [
      • American Society of Health System Pharmacists Inc.
      ], “Embase” and “Medline” were searched for combinations of the terms “nebulizer solution”, “inhalation”, “compatibility”, “stability”, “combination”, “HPLC”, “aerodynamic behaviour” and the drug substance names albuterol, ipratropium, cromolyn, budesonide, tobramycin, colistin and dornase alfa. “HPLC”(high-performance liquid chromatography) was searched for, because it is a common analytical method to determine compatibility or stability of admixtures. Besides the databases, in pharmacy departments commonly used reference books like the “AHFS Drug Information” [
      • American Society of Health-System Pharmacists Inc.
      AHFS drug information 2003.
      ], and the “Handbook on Injectable Drugs” [
      • Trissel L.A.
      Handbook on injectable drugs.
      ] and the database “Drugdex” [
      ] were searched for information concerning acetylcysteine and the drugs given above.
      For each inhalation solution/suspension that is licensed in Germany, the prescribing information for health care professionals (“Fachinformation”) was consulted for details concerning compatibility in nebulizers. Additionally, manufacturers of approved nebulizable medications of the drug substances albuterol, ipratropium, cromolyn, budesonide, tobramycin, colistin, dornase alfa, acetylcysteine and ambroxole were contacted and asked for information about the compatibility of their drug with other inhalation solutions/suspensions in nebulizers.

      3. Results

      The results are shown for each of the different drugs.
      The prescribing information and information obtained from the manufacturers is correct for the brands that are licensed in Germany.

      3.1 Albuterol

      The prescribing information for brands of albuterol contains no information about compatibility with other nebulizable medications. The prescribing information for Mucosolvan® inhalation solution 15 mg/2 mL (brand of ambroxole) contains the information that it can be mixed with adrenergic bronchodilators. The manufacturer of Sultanol® (brand of albuterol) told us that the inhalation solution is compatible with solutions of ipratropium (Atrovent®), cromolyn (Intal®), ambroxole (Mucosolvan®) and acetylcysteine (Fluimucil®) [personal communication, Glaxo SmithKline, Bad Oldesloe, Germany].
      According to the albuterol monograph in AHFS Drug Information [
      • American Society of Health-System Pharmacists Inc.
      AHFS drug information 2003.
      ], physical and chemical compatibility of albuterol admixtures has not been established. On the other hand, the ipratropium monograph states that admixtures of albuterol and ipratropium are chemically and physically stable for 1 h. Moreover, in the US, a combination of albuterol 2.5 mg and ipratropium bromide 0.5 mg in 3 mL unit-dose polyethylene vials (DuoNeb®) is commercially available.
      Drugdex [
      ] mentions that an admixture of albuterol and tobramycin is physically and chemically stable [
      • Gooch M.D.
      Stability of albuterol and tobramycin when mixed for aerosol administration.
      ].
      The primary literature on the physical and chemical stability of admixtures containing albuterol is summarized in Table 2.
      Table 2Compatibility of admixtures of albuterol inhalation solutions with other drugs for inhalation
      Admixed inhalation solution/suspensionStudy conditionsResultReference
      Ipratropium bromide (62.5 μg/mL)Storage: at RT or 45 °C/65 °C/85 °CCompatible storage life (loss of ipratropium ≤10%) 18 months at 20 °C, 3.8 years at 3–8 °C
      • Nagtegaal J.E.
      • De Jong A.
      • De Waard W.J.
      • Van der Meer Y.G.
      Formulation and shelf life of two solutions for inhalation.
      Determination: days 1 to 5, weekly for 6 months, every 3 months for 1 year (for RT)
      Method: HPLC
      Ipratropium bromide (62.5 μg/mL)+Cromolyn (5 mg/mL)Storage: at RT or 45 °C/65 °C/85 °CCompatible storage life (loss of ipratropium ≤10%) 10 months at 20 °C, 1.9 years at 3–8 °C
      • Nagtegaal J.E.
      • De Jong A.
      • De Waard W.J.
      • Van der Meer Y.G.
      Formulation and shelf life of two solutions for inhalation.
      Determination: days 1 to 5, weekly for 6 months, every 3 months for 1 year (for RT)
      Method: HPLC
      Ipratropium bromide (Atrovent® 250 μg/mL), mixed volume ratio 1:1Storage: 5 daysCompatible (loss ≤10%)
      • Jacobson G.A.
      • Peterson G.M.
      Stability of ipratropium bromide and salbutamol nebuliser admixtures.
      Protected from light: 4±0.5 °C/22±0.25 °C
      Fluorescent light: 22±0.25 °C
      Determination: days 0/1/2/5
      Method: HPLC
      Ipratropium (Atrovent® 250 μg/mL)+Cromolyn (Intal® 20 mg/2 mL); mixed volume ratio 1:1:1Storage: RTCompatible (loss ≤10%)
      • Iacono M.
      • Johnson G.J.
      • Bury R.W.
      An investigation of the compatibility of ipratropium and sodium cromoglycate nebuliser solutions.
      Determination: 0/about every 12 min for 1 h
      Method: HPLCOpacity for 48 h (Intal®+Atrovent®)
      Cromolyn (Intal® 1%); admixture: 0.5 mL Ventolin®+2 mL Intal®+1 mL NaCl 0.9%Storage: RTCompatible (loss ≤2%)
      • Emm T.
      • Metcalf J.E.
      • Lesko L.J.
      • Chai M.F.
      Update on the physical–chemical compatibility of cromolyn sodium inhalation solution: bronchodilator inhalant solution admixtures.
      Determination: 0/30/60/90 min
      Method: HPLC
      Tobramycin (Nebcin®, 40 mg/mL); admixture: 0.5 mL Ventolin®+1 mL Nebcin®+2 mL NaCl 0.9%Storage: 4 °C, glass containerCompatible (at 2–8 °C) (loss ≤10%)
      • Gooch M.D.
      Stability of albuterol and tobramycin when mixed for aerosol administration.
      Determination: days 0/1/2/7
      Methods: HPLC (albuterol), fluorescent immunoassay (tobramycin)
      Tobramycin (no information given about studied concentrations)Storage: not knownCompatible

      Hood JC, White TS. Stability of selected antibiotics solutions with albuterol and ipratropium inhalation solutions in the treatment of pulmonary infections. ASHP-Midyear-Clinical-Meeting 33 (1998) P-43E. Personal communication.

      Determination: over 24 h
      Methods: not known
      Tobramycin+Ipratropium (no information given about studied concentrations)Storage: not knownCompatible

      Hood JC, White TS. Stability of selected antibiotics solutions with albuterol and ipratropium inhalation solutions in the treatment of pulmonary infections. ASHP-Midyear-Clinical-Meeting 33 (1998) P-43E. Personal communication.

      Determination: over 24 h
      Method: not known
      Colistin (Coly-Mycin M Parenteral® 4.5 million units vials, 1 million units or 33.3 mg/mL); admixture: 1 mL albuterol+1 mL Coly-Mycin M (+1 mL NaCl 0.9% for colistin determination)Storage: RTCompatible for 1 h for solution without preservatives, cloudiness due to BAC; loss: albuterol 7% (1 h), 14% (24 h), colistin 2% (1 h)
      • Roberts G.W.
      • Badcock N.R.
      • Jarvinen A.O.
      Cystic fibrosis inhalation therapy: stability of a combined salbutamol/colistin solution.
      Determination: 1 h, 24 h (albuterol only)
      Methods: HPLC (albuterol), bioassay (colistin)
      Budesonide (Pulmicort® 0.25 mg/2 mL or 0.5 mg/2 mL); admixture: 0.5 mL Proventil®+2 mL Pulmicort® or 3 mL Xopenex®+2 mL Pulmicort®Storage: RTCompatible (loss ≤10%)
      • McKenzie J.E.
      • Cruz Rivera M.
      Compatibility of budesonide inhalation suspension with four nebulizing solutions.
      Determination: 0/5/15/30 min
      Method: HPLC
      Budenoside (Pulmicort® 0.25 mg/2 mL or 0.5 mg/2 mL); admixture: 0.5 mL albuterol+2 mL Pulmicort®Storage: RTCompatible (loss ≤10%)
      • Smaldone G.C.
      • McKenzie J.
      • Cruz Rivera M.
      • Hoag J.
      Budesonide inhalation suspension is chemically compatible with other nebulizing formulations (Abstract).
      Determination: 0/5/15/30 min
      Method: HPLC
      Used brands of albuterol inhalation solutions:
      • Nagtegaal J.E.
      • De Jong A.
      • De Waard W.J.
      • Van der Meer Y.G.
      Formulation and shelf life of two solutions for inhalation.
      : albuterol sulfate 1.5 mg/mL,
      • Gooch M.D.
      Stability of albuterol and tobramycin when mixed for aerosol administration.
      ,
      • Jacobson G.A.
      • Peterson G.M.
      Stability of ipratropium bromide and salbutamol nebuliser admixtures.
      ,
      • Emm T.
      • Metcalf J.E.
      • Lesko L.J.
      • Chai M.F.
      Update on the physical–chemical compatibility of cromolyn sodium inhalation solution: bronchodilator inhalant solution admixtures.
      : Ventolin® 0.5%,
      • Iacono M.
      • Johnson G.J.
      • Bury R.W.
      An investigation of the compatibility of ipratropium and sodium cromoglycate nebuliser solutions.
      : Respolin® Respirator Solution 5 mg/mL,
      • McKenzie J.E.
      • Cruz Rivera M.
      Compatibility of budesonide inhalation suspension with four nebulizing solutions.
      : Proventil® 5 mg/mL or Xopenex® 0.63 mg/3 mL or 1.25 mg/3 mL,
      • Smaldone G.C.
      • McKenzie J.
      • Cruz Rivera M.
      • Hoag J.
      Budesonide inhalation suspension is chemically compatible with other nebulizing formulations (Abstract).
      : albuterol 5 mg/mL,
      • Roberts G.W.
      • Badcock N.R.
      • Jarvinen A.O.
      Cystic fibrosis inhalation therapy: stability of a combined salbutamol/colistin solution.
      : salbutamol 5 mg/mL respirator solution.
      RT=room temperature.
      In several studies, compatibility and stability of admixtures of albuterol and ipratropium are shown. Nagtegaal et al. [
      • Nagtegaal J.E.
      • De Jong A.
      • De Waard W.J.
      • Van der Meer Y.G.
      Formulation and shelf life of two solutions for inhalation.
      ] manufactured two different combination inhalation solutions in glass ampoules free of preservatives. The combination of albuterol and ipratropium was more stable than the combination of albuterol, ipratropium and cromolyn, with ipratropium as the stability limiting drug substance. Jacobson and Peterson [
      • Jacobson G.A.
      • Peterson G.M.
      Stability of ipratropium bromide and salbutamol nebuliser admixtures.
      ] investigated the compatibility of commercially available albuterol and ipratropium inhalation solutions. Both brands contained benzalkonium chloride (BAC) as preservative. The ipratropium inhalation solution also contained ethylenediaminetetraacetic acid (EDTA). Under various storage conditions, the admixture was found to be physically and chemically stable over 5 days.
      Gooch [
      • Gooch M.D.
      Stability of albuterol and tobramycin when mixed for aerosol administration.
      ] demonstrated that an admixture of albuterol inhalation solution and tobramycin infusion solution concentrate remained physically and chemically stable over seven days when stored under refrigeration. Hood and White [

      Hood JC, White TS. Stability of selected antibiotics solutions with albuterol and ipratropium inhalation solutions in the treatment of pulmonary infections. ASHP-Midyear-Clinical-Meeting 33 (1998) P-43E. Personal communication.

      ] documented physical and chemical stability of an albuterol and tobramycin admixture over 24 h; addition of ipratropium inhalation solution did not impair stability.
      According to Roberts et al. [
      • Roberts G.W.
      • Badcock N.R.
      • Jarvinen A.O.
      Cystic fibrosis inhalation therapy: stability of a combined salbutamol/colistin solution.
      ], cloudiness developed in an admixture of colistin inhalation solution and albuterol inhalation solution. The albuterol inhalation solution used was a multidose product containing BAC. The cloudiness persisted for at least 10 h but by 24 h the admixture had regained complete clarity. The cloudiness was attributed to an interaction of BAC with colistin. Cloudiness was more pronounced and lasted longer with increasing concentrations of BAC and when the admixtures were stored at lower temperatures. The effect of cloudiness on the aerodynamic behaviour of the admixture is unknown. Mixing colistin and preservative-free unit-dose albuterol inhalation solution avoids this problem and the admixture is chemically stable over 1 h.

      3.2 Cromolyn

      The authors are aware that cromolyn is not a standard therapy in cystic fibrosis. But in the interview conducted at our CF centre, 7% of the patients inhaling more than one nebulizable drug reported to inhale cromolyn.
      Prescribing information for brands of cromolyn contains no advice for mixing with other inhalation solutions. The prescribing information for Atrovent® (brand of ipratropium) states that the drug should not be mixed with cromolyn inhalation solution as precipitation can occur. The manufacturer of Intal® (brand of cromolyn) informed us, that incompatibilities with other inhalation solutions are not known [personal communication Fisons/Rhône-Poulenc Rorer, Cologne, Germany].
      According to the cromolyn monograph in AHFS Drug Information [
      • American Society of Health-System Pharmacists Inc.
      AHFS drug information 2003.
      ], the physical and chemical stability of cromolyn admixtures is unknown. On the other hand, the ipratropium monograph states that admixtures of cromolyn and ipratropium inhalation solutions are chemically and physically stable over 1 h.
      Drugdex [
      ] cites the study of Lesko and Miller [
      • Lesko L.J.
      • Miller A.K.
      Physical chemical compatibility of cromolyn sodium inhalation solution – bronchodilator inhalant solution admixtures.
      ] and reports that admixtures of cromolyn and various adrenergic bronchodilators as well as acetylcysteine inhalation solutions are physically and chemically stable.
      The primary literature on the physical and chemical stability of admixtures containing cromolyn inhalation solutions is summarized in Table 3.
      Table 3Compatibility of admixtures of cromolyn inhalation solutions with other drugs for inhalation
      Admixed inhalation solution/suspensionStudy conditionsResultReference
      Ipratropium bromide (62.5 μg/mL)+Albuterol sulfate (1.5 mg/mL)Storage: at RT or 45 °C/65 °C/85 °CCompatible storage life (loss of ipratropium ≤10%) 10 months at 20 °C, 1.9 years at 3–8 °C
      • Nagtegaal J.E.
      • De Jong A.
      • De Waard W.J.
      • Van der Meer Y.G.
      Formulation and shelf life of two solutions for inhalation.
      Determination: days 1 to 5, weekly for 6 months, every 3 months for 1 year (for RT)
      Method: HPLC
      Ipratropium bromide (Atrovent® 250 μg/mL); mixed volume ratio 1:1Storage: RTCompatible (loss ≤10%) opacity for 48 h (Intal®+Atrovent®)
      • Iacono M.
      • Johnson G.J.
      • Bury R.W.
      An investigation of the compatibility of ipratropium and sodium cromoglycate nebuliser solutions.
      Determination: 0/about every 12 min for 1 h
      Method: HPLC
      Ipratropium bromide (Atrovent® 250 μg/mL)+Albuterol sulfate (Respolin® Respirator Solution 5 mg/mL); mixed volume ratio 1:1:1Storage: RTCompatible (loss ≤10%) cloudiness for 48 h (Intal®+Atrovent®)
      • Iacono M.
      • Johnson G.J.
      • Bury R.W.
      An investigation of the compatibility of ipratropium and sodium cromoglycate nebuliser solutions.
      Determination: 0/about every 12 min for 1 h
      Method: HPLC
      Albuterol sulfate (Ventolin® 0.5%); admixture: 2 mL Intal®+0.5 mL Ventolin®+1 mL NaCl 0.9%Storage: RTCompatible (loss ≤2%)
      • Emm T.
      • Metcalf J.E.
      • Lesko L.J.
      • Chai M.F.
      Update on the physical–chemical compatibility of cromolyn sodium inhalation solution: bronchodilator inhalant solution admixtures.
      Determination: 0/30/60/90 min
      Method: HPLC
      Orciprenaline sulfate (Alupent® 5%, multidose, no metabisulfite or Alupent® 0.6% inhalation solution); admixture: 2 mL Intal®+0.3 mL Alupent® 5%+2.5 mL NaCl 0.9% or 2 mL Intal®+2.5 mL Alupent® 0.6%Storage: RTCompatible (loss ≤2%)
      • Emm T.
      • Metcalf J.E.
      • Lesko L.J.
      • Chai M.F.
      Update on the physical–chemical compatibility of cromolyn sodium inhalation solution: bronchodilator inhalant solution admixtures.
      Determination: 0/30/60/90 min
      Method: HPLC
      Orciprenaline sulfate (Alupent® 5%); admixture: 2 mL Intal®+0.3 mL Alupent® 5%+2.5 mL NaCl 0.9%Storage: RTCompatible (loss ≤10%)
      • Lesko L.J.
      • Miller A.K.
      Physical chemical compatibility of cromolyn sodium inhalation solution – bronchodilator inhalant solution admixtures.
      Determination: 0/15/30/45/60 min
      Method: HPLC
      Terbutaline sulfate (Brethine® 0.1%); admixture: 2 mL Intal®+0.5 mL Brethine® 0.1%Storage: RTCompatible (loss ≤10%)
      • Lesko L.J.
      • Miller A.K.
      Physical chemical compatibility of cromolyn sodium inhalation solution – bronchodilator inhalant solution admixtures.
      Determination: 0/15/30/45/60 min
      Method: HPLC
      Acetylcysteine (Mucomyst® 20%); admixture: 2 mL Intal®+ 2 mL Mucomyst® 20%Storage: RTCompatible (loss ≤10%)
      • Lesko L.J.
      • Miller A.K.
      Physical chemical compatibility of cromolyn sodium inhalation solution – bronchodilator inhalant solution admixtures.
      Determination: 0/15/30/45/60 min
      Method: HPLC
      Budesonide (Pulmicort® 0.25 mg/2 mL or 0.5 mg/2 mL); admixture: 2 mL Intal®+2 mL Pulmicort®Storage: RTCompatible (loss ≤10%)
      • Smaldone G.C.
      • McKenzie J.
      • Cruz Rivera M.
      • Hoag J.
      Budesonide inhalation suspension is chemically compatible with other nebulizing formulations (Abstract).
      ,
      • McKenzie J.E.
      • Cruz Rivera M.
      Compatibility of budesonide inhalation suspension with four nebulizing solutions.
      Determination: 0/5/15/30 min
      Method: HPLC
      Used brands of cromolyn inhalation solutions:
      • Nagtegaal J.E.
      • De Jong A.
      • De Waard W.J.
      • Van der Meer Y.G.
      Formulation and shelf life of two solutions for inhalation.
      : cromolyn 5 mg/mL,
      • Lesko L.J.
      • Miller A.K.
      Physical chemical compatibility of cromolyn sodium inhalation solution – bronchodilator inhalant solution admixtures.
      ,
      • Iacono M.
      • Johnson G.J.
      • Bury R.W.
      An investigation of the compatibility of ipratropium and sodium cromoglycate nebuliser solutions.
      ,
      • Emm T.
      • Metcalf J.E.
      • Lesko L.J.
      • Chai M.F.
      Update on the physical–chemical compatibility of cromolyn sodium inhalation solution: bronchodilator inhalant solution admixtures.
      ,
      • Smaldone G.C.
      • McKenzie J.
      • Cruz Rivera M.
      • Hoag J.
      Budesonide inhalation suspension is chemically compatible with other nebulizing formulations (Abstract).
      ,
      • McKenzie J.E.
      • Cruz Rivera M.
      Compatibility of budesonide inhalation suspension with four nebulizing solutions.
      : Intal® 20 mg/2 mL.
      RT=room temperature.
      The compatibility of cromolyn, albuterol and ipratropium inhalation solutions has already been described above [
      • Nagtegaal J.E.
      • De Jong A.
      • De Waard W.J.
      • Van der Meer Y.G.
      Formulation and shelf life of two solutions for inhalation.
      ]. Iacono et al. [
      • Iacono M.
      • Johnson G.J.
      • Bury R.W.
      An investigation of the compatibility of ipratropium and sodium cromoglycate nebuliser solutions.
      ] studied admixtures of cromolyn and ipratropium inhalation solutions with and without addition of albuterol inhalation solutions. Cloudiness developed instantly on mixing cromolyn and ipratropium inhalation solutions (Intal® and Atrovent®). The mixture cleared within 48 h and no precipitate was detected. The authors then mixed aqueous solutions of BAC or EDTA (0.01%–2%) with Intal® or an aqueous solution of cromolyn (20 mg/2 mL) as well as Atrovent® with an aqueous solution of cromolyn. No cloudiness was observed. The authors concluded that cloudiness was not related to pH or preservatives contained in Atrovent® solution (BAC, EDTA). They attributed the cloudiness to an unknown excipient in Intal®.
      According to its own studies, the manufacturer of Intal® attributed cloudiness of Intal® and Atrovent® admixtures to BAC [
      • Turner M.
      Compatibility of nebuliser solutions (letter).
      ]. BAC formed an oily, non-crystalline complex with cromolyn, depending on the BAC concentration. They suggested that Iacono et al. [
      • Iacono M.
      • Johnson G.J.
      • Bury R.W.
      An investigation of the compatibility of ipratropium and sodium cromoglycate nebuliser solutions.
      ] might have used supersaturated solutions, resulting in delayed crystallization. Studies conducted by the manufacturer reconfirmed compatibility of admixtures of Intal® with Atrovent®as well as with Ventolin® or Respolin® (albuterol), Alupent® (orciprenaline), Berotec® (fenoterol), and Bricanyl® (terbutaline), each in the recommended dosage for up to 15 h [
      • Turner M.
      Compatibility of nebuliser solutions (letter).
      ].
      Emm et al. [
      • Emm T.
      • Metcalf J.E.
      • Lesko L.J.
      • Chai M.F.
      Update on the physical–chemical compatibility of cromolyn sodium inhalation solution: bronchodilator inhalant solution admixtures.
      ] studied the compatibility of admixtures of cromolyn and albuterol or orciprenaline inhalation solutions in various concentrations. In two of three admixtures of cromolyn and orciprenaline 0.6% (Intal® and Alupent®) the content of the active substances declined by more than 2% after 90 min (cromolyn 8.4%, orciprenaline 10%). The authors attributed these results to analytical error rather than degradation as one of the three samples of this admixture demonstrated no change in drug concentration.
      In the 1980s, Lesko and Miller [
      • Lesko L.J.
      • Miller A.K.
      Physical chemical compatibility of cromolyn sodium inhalation solution – bronchodilator inhalant solution admixtures.
      ] investigated the compatibility of cromolyn and various adrenergic bronchodilators or acetylcysteine inhalation solutions. In some admixtures containing cromolyn and an adrenergic bronchodilator, the authors observed discoloration and precipitation after 24 h storage at room temperature without light protection. They attributed these changes to oxidation of the adrenergic bronchodilators.

      3.3 Budesonide

      The prescribing information for Pulmicort® inhalation suspensions (brand of budesonide) states that the inhalation suspension can be mixed with other inhalation solutions (e.g. terbutaline, albuterol, cromolyn, ipratropium). In a telephone interview representatives of the manufacturer (Astra-Zeneca GmbH, Wedel, Germany) informed us that cloudiness occurred in admixtures of Pulmicort® with cromolyn (Intal®) or ambroxole (Mucosolvan®). This information is not included in the prescribing information and is not corroborated by the studies cited below [
      • Smaldone G.C.
      • McKenzie J.
      • Cruz Rivera M.
      • Hoag J.
      Budesonide inhalation suspension is chemically compatible with other nebulizing formulations (Abstract).
      ,
      • McKenzie J.E.
      • Cruz Rivera M.
      Compatibility of budesonide inhalation suspension with four nebulizing solutions.
      ].
      AHFS Drug Information [
      • American Society of Health-System Pharmacists Inc.
      AHFS drug information 2003.
      ] includes no monograph on budesonide inhalation solution. Drugdex [
      ] contained no information about compatibility of admixtures of budesonide inhalation suspension with other inhalation solutions.
      The primary literature on the physical and chemical stability of admixtures containing budesonide inhalation suspension is summarized in Table 4.
      Table 4Compatibility of admixtures of budesonide inhalation suspension with other inhalative drugs
      Admixed inhalation solutionStudy conditionsResultReference
      Albuterol (Proventil® 5 mg/mL or Xopenex® 0.63 mg/3 mL or 1.25 mg/3 mL); admixture: 2 mL Pulmicort®+0.5 mL Proventil® or 2 mL Pulmicort®+3 mL Xopenex®Storage: RTCompatible (loss ≤10%)
      • McKenzie J.E.
      • Cruz Rivera M.
      Compatibility of budesonide inhalation suspension with four nebulizing solutions.
      Determination: 0/5/15/30 min
      Method: HPLC
      Albuterol (5 mg/mL); admixture: 2 mL Pulmicort®+0.5 mL albuterolStorage: RTCompatible (loss ≤10%)
      • Smaldone G.C.
      • McKenzie J.
      • Cruz Rivera M.
      • Hoag J.
      Budesonide inhalation suspension is chemically compatible with other nebulizing formulations (Abstract).
      Determination: 0/5/15/30 min
      Method: HPLC
      Cromolyn (Intal® 20 mg/mL); admixture: 2 mL Pulmicort®+2 mL Intal®Storage: RTCompatible (loss ≤10%)
      • Smaldone G.C.
      • McKenzie J.
      • Cruz Rivera M.
      • Hoag J.
      Budesonide inhalation suspension is chemically compatible with other nebulizing formulations (Abstract).
      ,
      • McKenzie J.E.
      • Cruz Rivera M.
      Compatibility of budesonide inhalation suspension with four nebulizing solutions.
      Determination: 0/5/15/30 min
      Method: HPLC
      Ipratropium bromide (Atrovent® 0.2 mg/mL); admixture: 2 mL Pulmicort®+2.5 mL Atrovent®Storage: RTCompatible (loss ≤10%)
      • Smaldone G.C.
      • McKenzie J.
      • Cruz Rivera M.
      • Hoag J.
      Budesonide inhalation suspension is chemically compatible with other nebulizing formulations (Abstract).
      Determination: 0/5/15/30 min
      Method: HPLC
      Ipratropium bromide (Atrovent® 0.25 mg/mL); mixed volume ratio 2:1 (Pulmicort®:Atrovent®)Storage: 22–25 °C, protected from lightCompatible

      Grönberg S, Magnusson P, Bladh N. Chemical compatibility of budesonide inhalation suspension (Pulmicort™) with other nebulization products (Abstract). Meeting of the American Thoracic Society 2001. Personal communication.

      Determination: 0/18 h
      Method: HPLC
      Fenoterol hydrobromide (Berotec® 5 mg/mL); mixed volume ratio 8:1 (Pulmicort®:Berotec®)Storage: 22–25 °C, protected from lightCompatible

      Grönberg S, Magnusson P, Bladh N. Chemical compatibility of budesonide inhalation suspension (Pulmicort™) with other nebulization products (Abstract). Meeting of the American Thoracic Society 2001. Personal communication.

      Determination: 0/18 h
      Method: HPLC
      Ipratropium bromide (Duovent® 0.125 mg/mL)+Fenoterol hydrobromide (Duovent® 0.31 mg/mL); mixed volume ratio 1:1 (Pulmicort®:Duovent®)Storage: 22–25 °C, protected from lightCompatible

      Grönberg S, Magnusson P, Bladh N. Chemical compatibility of budesonide inhalation suspension (Pulmicort™) with other nebulization products (Abstract). Meeting of the American Thoracic Society 2001. Personal communication.

      Determination: 0/18 h
      Method: HPLC
      Acetylcysteine (Lysomucil® 100 mg/mL); mixed volume ratio 2:3 (Pulmicort®:Lysomucil®)Storage: 22–25 °C, protected from lightCompatible

      Grönberg S, Magnusson P, Bladh N. Chemical compatibility of budesonide inhalation suspension (Pulmicort™) with other nebulization products (Abstract). Meeting of the American Thoracic Society 2001. Personal communication.

      Determination: 0/18 h
      Method: HPLC
      Used brands of budesonide inhalation suspension:
      • Smaldone G.C.
      • McKenzie J.
      • Cruz Rivera M.
      • Hoag J.
      Budesonide inhalation suspension is chemically compatible with other nebulizing formulations (Abstract).
      ,
      • McKenzie J.E.
      • Cruz Rivera M.
      Compatibility of budesonide inhalation suspension with four nebulizing solutions.
      : Pulmicort® 0.25 mg/2 mL or 0.5 mg/2 mL,

      Grönberg S, Magnusson P, Bladh N. Chemical compatibility of budesonide inhalation suspension (Pulmicort™) with other nebulization products (Abstract). Meeting of the American Thoracic Society 2001. Personal communication.

      : Pulmicort® 0.5 mg/mL.
      RT=room temperature.
      Smaldone et al. [
      • Smaldone G.C.
      • McKenzie J.
      • Cruz Rivera M.
      • Hoag J.
      Budesonide inhalation suspension is chemically compatible with other nebulizing formulations (Abstract).
      ] and McKenzie et al. [
      • McKenzie J.E.
      • Cruz Rivera M.
      Compatibility of budesonide inhalation suspension with four nebulizing solutions.
      ] demonstrated chemical and physical compatibility of admixtures of budesonide with albuterol, cromolyn or ipratropium inhalation solutions. Gronberg et al. [

      Grönberg S, Magnusson P, Bladh N. Chemical compatibility of budesonide inhalation suspension (Pulmicort™) with other nebulization products (Abstract). Meeting of the American Thoracic Society 2001. Personal communication.

      ] studied admixtures of budesonide with ipratropium and/or fenoterol or acetylcysteine inhalation solutions. All of them were compatible.

      3.4 Ipratropium

      The prescribing information for Atrovent® (brand of ipratropium) states that mixing and simultaneous inhalation of ipratropium and ambroxole (e.g. Mucosolvan®) and fenoterol (Berotec® LS 0.1%, no longer available on the German market) is feasible. Mixing Atrovent® with cromolyn is not recommended, because of known incompatibility (see above). The prescribing information for Berodual® inhalation solution (brand of ipratropium and fenoterol) is consistent with respect to the compatibility with Mucosolvan® (brand of ambroxole). The monograph on “ipratropium bromide” in Drugdex [
      ] supplies no information about the stability of admixtures of ipratropium inhalation solution. However, there are monographs on nebulizable combination products of ipratropium and albuterol or fenoterol. The AHFS Drug Information [
      • American Society of Health-System Pharmacists Inc.
      AHFS drug information 2003.
      ] monograph on ipratropium reports compatibility of an admixture with orciprenaline sulfate over 1 h.
      Tzung-Yiet et al. found an admixture of Acetein® (brand of N-acetylcysteine sodium 352.4 mg/2 mL) with Atrovent® (brand of ipratropium bromide 500 μg/2 mL) to be compatible for 1 h; admixture with Berotec® (brand of fenoterol hydrobromide 1.25 mg/2 mL) was stable for at least 7 h [
      • Tzung-Yiet L.
      • Chi-Ming C.
      • Chun-Nin L.
      • Yi-Chun C.
      • Hsiang-Yin C.
      Compatibility and osmolality of inhaled N-acetylcysteine nebulizing solution with fenoterol and ipratropium.
      ].

      3.5 Acetylcysteine and colistin

      Compatibility over 1 h has been reported for admixtures of Mucomyst® (brand of acetylcysteine 1 g/5 mL) and Netromicine® (brand of netilmicin 100 mg/1 mL) or Celestene® (brand of betamethasone 4 mg/1 mL), when test solutions were stored at room temperature [
      • Rieutord A.
      • Arnaud P.
      • Dauphin J.F.
      • Brion F.
      Stability and compatibility of an aerosol mixture including N-acetylcysteine, netilmicin and betamethasone.
      ]. According to the AHFS Drug Information [
      • American Society of Health-System Pharmacists Inc.
      AHFS drug information 2003.
      ] monograph on acetylcysteine and the prescribing information for Fluimucil® (brand of acetylcysteine), admixtures with some nebulizable antibiotic drugs are physically and/or chemically unstable. Drugdex [
      ] states that Mucomyst® 10% is compatible with colistin 37.5 mg/mL, based on the Mucomyst product information. Immediate use after mixing is recommended. The prescribing information for Colistin zur Inhalation® (brand of colistin) states that precipitation in admixtures with other nebulizable antibiotic drugs may occur.

      3.6 Tobramycin

      According to the prescribing information of Gernebcin® and TOBI® (brands of tobramycin) and the AHFS Drug Information [
      • American Society of Health-System Pharmacists Inc.
      AHFS drug information 2003.
      ] monograph on tobramycin sulfate, tobramycin inhalation solution should not be diluted or mixed with other drugs. Drugdex [
      ] includes a warning against mixing tobramycin and dornase alfa (Pulmozyme®) in addition to the above mentioned compatibility of tobramycin and albuterol admixture [
      • Gooch M.D.
      Stability of albuterol and tobramycin when mixed for aerosol administration.
      ].

      3.7 Dornase alfa

      The prescribing information for Pulmozyme® (brand of dornase alfa), Drugdex [
      ] and AHFS Drug Information [
      • American Society of Health-System Pharmacists Inc.
      AHFS drug information 2003.
      ] all consistently state that dornase alfa inhalation solution should not be diluted or mixed with other drug solutions in nebulizers.
      Aerodynammic behaviour of admixtures of nebulizer solutions has hardly been studied. According to our literature research, only in one study [
      • McKenzie J.
      • Gronberg S.
      • Cruz M.
      • Rivera J.
      Budesonide inhalation suspension can be nebulized with solutions containing albuterol sulphate (Poster).
      ] an admixture of budesonide (Pulmicort® 0.25 or 0.50 mg/2 mL) and albuterol (0.5 mL Proventil® solution for inhalation 0.5% in 2.5 mL sterile saline or 3 mL albuterol sulfate, USP inhalation solution, 0.083%) was nebulized. The authors describe an increase of budesonide delivery and nebulization time with increasing volume of nebulizer charge.

      4. Discussion

      Our own experience, together with inquiries among colleagues and patients, revealed considerable demand for information about the compatibility of drug solutions and suspensions for oral inhalation (which we have described as “inhalation solutions”). However, the available data are limited and inconsistent.
      The well-known handbook on drug compatibility, “Handbook of Injectable Drugs [
      • Trissel L.A.
      Handbook on injectable drugs.
      ]”, considers injectable drugs only. No information is given about the compatibility of inhalation solution admixtures. In prescribing information for licensed inhalation solutions, there is no consistent standard regarding information about compatibility of admixtures. Moreover, few studies on the physical and chemical stability of inhalation solution admixtures have been published and the quality of studies and reviews [
      • Joseph J.C.
      Compatibility of inhalation solution admixtures.
      ,
      • Roberts G.W.
      • Rossi S.O.P.
      Compatibility of nebuliser solutions.
      ] varies. In some cases, the compatibility of inhalation solutions is stated without any supporting experimental data [
      • Allen L.V.
      Combination solutions for bronchospasm.
      ,
      • Harriman A.M.
      • Purcell N.
      • Fleming S.
      • Daly M.J.
      Can we mix nebuliser solutions?.
      ]. In summary, the problem of compatibility of inhalation solution admixtures receives little attention at present and has not been comprehensively researched at all.
      Strictly speaking, compatibility demonstrated in experimental studies can only be accepted for the concentrations and volumes tested. In addition, transferring results of experimental studies from one drug product to another is difficult as preservatives and other excipients can vary and cause incompatibilities. For example the preservative BAC causes cloudiness in admixtures containing cromolyn [
      • Iacono M.
      • Johnson G.J.
      • Bury R.W.
      An investigation of the compatibility of ipratropium and sodium cromoglycate nebuliser solutions.
      ,
      • Turner M.
      Compatibility of nebuliser solutions (letter).
      ,
      • Roberts G.W.
      • Rossi S.O.P.
      Compatibility of nebuliser solutions.
      ] or colistin [
      • Roberts G.W.
      • Badcock N.R.
      • Jarvinen A.O.
      Cystic fibrosis inhalation therapy: stability of a combined salbutamol/colistin solution.
      ]. The cloudiness is due to an oily, non-crystalline complex [
      • Iacono M.
      • Johnson G.J.
      • Bury R.W.
      An investigation of the compatibility of ipratropium and sodium cromoglycate nebuliser solutions.
      ,
      • Turner M.
      Compatibility of nebuliser solutions (letter).
      ,
      • Roberts G.W.
      • Rossi S.O.P.
      Compatibility of nebuliser solutions.
      ] and increases with increasing concentrations of BAC [
      • Turner M.
      Compatibility of nebuliser solutions (letter).
      ,
      • Roberts G.W.
      • Rossi S.O.P.
      Compatibility of nebuliser solutions.
      ]. The influence of complex formation on the aerodynamic behaviour of the admixtures has not been studied [
      • Roberts G.W.
      • Rossi S.O.P.
      Compatibility of nebuliser solutions.
      ].
      Furthermore, it is questionable whether the quantitative analysis of drug substances in samples taken from the admixture containers is adequate, or whether the drug content needs to be determined in the aerosols. Owsley et al. [
      • Owsley H.D.
      • Rusho W.J.
      Compatibility of common respiratory therapy drug combinations.
      ] questioned the reported compatibility of admixtures containing cromolyn [
      • Lesko L.J.
      • Miller A.K.
      Physical chemical compatibility of cromolyn sodium inhalation solution – bronchodilator inhalant solution admixtures.
      ,
      • Emm T.
      • Metcalf J.E.
      • Lesko L.J.
      • Chai M.F.
      Update on the physical–chemical compatibility of cromolyn sodium inhalation solution: bronchodilator inhalant solution admixtures.
      ]. Using a filtration method (USP method for analyzing particulates in large volume parenterals [
      • United States Pharmacopeial Convention, Inc.
      The United States pharmacopeia.
      ]), 22 admixtures of various inhalation solutions were analyzed in samples taken 0, 5, 10, 20 min and 24 h after mixing. With a maximum allowed particle load of 50 particles ≥10 μm diameter or 5 particles ≥25 μm diameter per mL admixture, 19 of 22 admixtures were classified as incompatible, including all admixtures containing cromolyn. The authors [
      • Owsley H.D.
      • Rusho W.J.
      Compatibility of common respiratory therapy drug combinations.
      ] postulated that the mobile phase used in HPLC experiments may solve invisible precipitates, leading to erroneous results of unchanged drug content and an incorrect conclusion about compatibility. However, for inhalation solutions, the chosen limits of particle diameters of ≥10 μm and ≥25 μm may not be adequate. The portion of particles with a diameter >5 μm might have been even more relevant.
      In the European and the US pharmacopoeia [
      • United States Pharmacopeial Convention, Inc.
      The United States pharmacopeia.
      ,

      Pharmacopoeia European basic edition. 4th Ed. Deutscher Apotheker Verlag, Stuttgart, Govi-Verlag-Pharmazeutischer Verlag, Eschborn; 2002.

      ] analytical methods to determine the proportion of droplets and particles <5 μm in diameter are described. The US pharmacopoeia [
      • United States Pharmacopeial Convention, Inc.
      The United States pharmacopeia.
      ] requires that the particle size of the medication delivered must be carefully controlled, and the average diameter of the particles should be less than 5 μm. The European pharmacopoeia [

      Pharmacopoeia European 4th supplement. 4th Ed. Deutscher Apotheker Verlag, Stuttgart, Govi-Verlag-Pharmazeutischer Verlag, Eschborn; 2003

      ] only states that the size of aerosol particles to be inhaled is controlled so that a significant fraction is deposited in the lung.
      Even if the admixtures are physically and chemically compatible in the nebulizer cup, the aerodynamic behaviour may be influenced by mixing inhalation solutions. Questions such as droplet and particle size distribution in the aerosols and incompatibilities arising during nebulization of the admixtures remain to be addressed.
      Clay et al. [
      • Clay M.M.
      • Pavia D.
      • Newman S.P.
      • Lennard-Jones T.
      • Clarke S.W.
      Assessment of jet nebulisers for lung aerosol therapy.
      ] report that the temperature of the inhalation solutions in the nebulizer cup decreases to different extents during nebulization depending on the type of jet nebulizer used. When nebulizing 2 mL solution with compressed air at a flow of 4 L/min the temperature of the solution dropped up to 12 °C during the first 5 min and remained constant afterwards. It is not known whether this drop in temperature causes any changes in the compatibility of admixtures of inhalation solutions.
      Mixing of inhalation solutions increases the volume fill of the nebulizer cup and can affect drug delivery. The relationship between volume fill and total mass output and inhaled mass of nebulized medications needs to be considered in the admixtures. If nebulization is continued until the nebulizer runs to dryness, the percentage of drug loss decreases (dead volume remains the same) and nebulization duration increases with increasing volume fill [
      • Boe J.
      • Dennis J.H.
      • O'Driscoll B.R.
      • Bauer T.T.
      • Carone M.
      • Dautzenberg B.
      • et al.
      For the society task force on the use of nebulizers. European Respiratory Society guidelines on the use of nebulizers.
      ,
      • Clay M.M.
      • Pavia D.
      • Newman S.P.
      • Lennard-Jones T.
      • Clarke S.W.
      Assessment of jet nebulisers for lung aerosol therapy.
      ,
      • McKenzie J.
      • Gronberg S.
      • Cruz M.
      • Rivera J.
      Budesonide inhalation suspension can be nebulized with solutions containing albuterol sulphate (Poster).
      ,

      Smaldone GC, McKenzie J, Cruz Rivera M. Effect of nebulizer volume on drug delivery: budesonide inhalation suspension. Meeting of the American Thoracic Society, 2000. Personal communication.

      ]. The output rate over time is not constant but depends on the volume remaining in the nebulizer cup during nebulization [
      • Clay M.M.
      • Pavia D.
      • Newman S.P.
      • Lennard-Jones T.
      • Clarke S.W.
      Assessment of jet nebulisers for lung aerosol therapy.
      ]. In order to nebulize the same amount of drug compared to consecutive nebulization of single inhalation solutions, the used volume of single inhalation solutions might be lowered. Shortening the nebulization duration of admixtures might be another option. These questions need to be investigated. In addition, the type of nebulizer used is relevant, as the temperature drop during aerosolization, as well as parameters depending on the volume fill (loss of drug, nebulization duration, output rate) vary considerably between different types [
      • Boe J.
      • Dennis J.H.
      • O'Driscoll B.R.
      • Bauer T.T.
      • Carone M.
      • Dautzenberg B.
      • et al.
      For the society task force on the use of nebulizers. European Respiratory Society guidelines on the use of nebulizers.
      ,
      • Clay M.M.
      • Pavia D.
      • Newman S.P.
      • Lennard-Jones T.
      • Clarke S.W.
      Assessment of jet nebulisers for lung aerosol therapy.
      ].
      Finally, sterility of the admixtures during storage time needs to be considered. Admixtures usually contain no or insufficient concentrations of preservatives. To avoid microbiological contamination, even compatible admixtures should be prepared directly before use and surplus quantities should not be stored.

      5. Conclusion

      The evaluation of the published literature revealed that admixtures of various inhalation solutions are physico-chemically compatible and patients can be allowed to mix them (see Table 5: possible). As cromolyn and colistin are incompatible with the preservative BAC, the admixtures must be prepared with brands of inhalation solutions containing no preservatives.
      Table 5Admixture advices for commonly used drug solutions/suspensions in nebulizers
      Table thumbnail fx1
      For those admixtures of inhalation solutions where no information about compatibility is available or admixtures are not recommended by the manufacturer, the authors decided to perform compatibility studies. Results will be published in the near future. In addition to the compatibility studies the aerodynamic behaviour of compatible admixtures will be studied to ensure that simultaneous nebulization of admixtures is recommendable.

      Acknowledgments

      The authors wish to thank Dr. Frank Erdnüß for his help in preparing this manuscript.

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